The initial infective process of the malaria parasite in humans is between the invading parasite and hepatocytes of the host. In several studies, the portal for this invasion has implicated the heparin/heparan sulfate (H/HS) receptor systems. Heparin also inhibits the rosetting and cytoadhesion of parasitized Plasmodium falciparum erythrocytes (PfRBC) to normal RBC and the endothelium, and clears blockage of the microcirculation which ameliorates life-threatening symptoms of cerebral malaria when administered in children. - Early on, at NIH, we discovered that heparin assumed helical structures in solution. We classified the various sulfated glycosaminoglycan biopolymers (GAG, mucopolysaccharides) on the basis of the specificity of their optically active structures and demonstrated (AL Stone 1963/4 Biopolymers 2/3) that H/HS (and keratosulfate) comprise a Class of GAGs, separate from other GAG types. They are multifunctional physiological modulator biopolymers. They are found in most tissues of the body where they not only govern the level of activity/function of numerous normal proteins and cell systems, but they also seem to serve as receptors for various human pathogens in a mechanism(s) that needs further elucidation. -Malaria ranks in the top three deadliest diseases globally (more than 300 million clinical cases per year). 1-3% of the Pf parasites are highly virulent, causing severe and cerebral malaria and the death of about 2-3 million people per year (90 % young children). There is no preventive vaccine, and malaria parasites are increasingly resistant to anti-malarial drugs. We applied our combinatorial family of heparin-mimetic S-oligoS (See HD 001315-14) in a preliminary study to characterize their in vitro inhibition capacities against malaria parasites. This revealed that the heparin-based inhibition of P. yoelii sporozoite (freshly isolated from infected mosquitoes) invasion of hepatocytes was governed by a degree of structural specificity and was concentration dependent. Two highly active library Components were identified: Component 6 (mass = 7200) and Component 11 (mass = 3700) which displayed 43 and 56 percent inhibition at 3.5 and 5 micromolar, resp. We reported early on that CP11, as well as other Components of mass less than 5000, had negligible capacity to mimic heparin's anticoagulant activation of antithrombin against thrombin (which causes the occasional bleeding toxicity when pharmaceutical heparin is administered clinically). Thus, Cp11 was selected for development of an enlarged preparation of purified Cp11 for preclinical and clinical studies was undertaken and is ongoing to insure adequate fractionation with good yield for this relatively small-sized S-OligoS Component. Importantly, last year's efforts to renew our mutual Confidentiality Agreement were realized this year, and contribution of a large lot of heparin-mimetic pharmaceutical starting material for an additional preparation of our HIV-1 fusion inhibitor, SOLIS, was transferred and received from Munich, D.R.. This will enable newly devised enlarged preparations of Components Cp11 and Cp8A/8B, as well. -Structural studies will be extended and further developed on the Cp11: E.g., Studies on a specific tetrasaccharide structural motif of three xyloses and a glucuronic acid as a branch on the xylan chain (90 percent sulfated yielding a high negative charge density) which we have demonstrated for S-OligoS H/HS mimetic Components, and obtained spectroscopic evidence indicating an increase in the number of stable motifs with increasing mass;Spectroscopic examination for presence of alternative sugar ring conformation, which was demonstrated unequivocally in the SOLIS structure. Such alternate forms induce specific distance and angle alterations in the otherwise uniform S-OligoS chain properties. Such a motif could accommodate the subtle specific variations in geometries involving sulfates that are required for mutifunctional mimicry of the heparins. Elucidation of the Cp11 structure might enable application of advanced high throughput methods in further drug development. -Recently developed statistical analysis was used by clinicians to calculate findings (Science319:1603 2006) that HIV infection in malaria endemic regions is spread at a rate 8 percent higher than in other regions where HIV-AIDS is on the rise, and vise-versa, due to an unexplained vullnerability of either patient to the second pathogen. We had suggested previously that co-treatment of malaria and HIV-AIDS would be feasible because of the close similarity in the physicochemical proerties of the respective S-oligoS inhibitors. The preliminary studies on the combined dosing of the Cp11 and SOLIS (S-OligoS malaria parasite and HIV-1 inhibitors, resp.) in vitro indicated a decrease in SOLIS capacity to protect against fusion between the virus and target CMESS (CD4 human line). Given the complexity of the biological systems which may be involved, the data are currently interpreted based on various biological models to generate appropriate studies which will be conducted with the Cp11 to elucidate this interpathogenesis. the S-OligoS structure contains a tetrasaccharide motif motif of three xyloses and a glucuronic acid as a branch on the xylan chain i.e., -D-glucuronyl-alpha 1,2 beta 1,4 D-(xylyl)3 with one third or less of the GlcA being O-methylated. The sugars are within 90 percent sulfated yielding a high negative charge density. Such a motif could accommodate the subtle variations in geometries involving sulfates that are required for mutifunctional mimicry of the heparins.